My immediate goal is to establish myself as an independent investigator. My long-term goal is to be a well-established researcher whose expertise contributed to our understanding of drug dependence. The present proposal for career development award is designed to elucidate the involvement of 5-HT1A receptors in the development of cocaine dependence. Drug dependence develops over frequent drug abuse. Thus, it is reasonable to examine changes in the neuronal systems with which a drug interacts to understand the pathology of drug dependence. One of the hypotheses is that the emergence of a negative emotional state during drug withdrawal plays a key role in the development of drug dependence. Cocaine stimulates the monoamine systems including serotonin (5-HT). Dysfunctional 5-HT1A receptors have been implicated in depression, anxiety and dysphoria, which are the major cocaine withdrawal symptoms in humans. However, the involvement of 5-HT1A receptors in cocaine dependence is not well understood. Our laboratory established a rodent model of drug self-administration with extended access, which mimics an increasing drug intake in dependent humans. Therefore, the present proposal explores the role of 5-HT1A receptors in cocaine dependence using this rodent model. The hypothesis is that changes in 5-HT1A receptors are associated with increased cocaine self-administration and the manifestation of cocaine withdrawal in rats with extended access. Specific Aim 1 examines the role of 5-HT1A receptors in cocaine self-administration and cocaine withdrawal in rats with extended access using 5-HT1A receptor ligands. Specific Aim 2 investigates time-dependent changes in 5-HT1A receptors in the extended amygdala and raphe nuclei in rats with extended access using Western blot and immunofluorescence. Specific Aim 3 investigates the relationship between 5-HT1A receptors and comorbidity of depression and cocaine dependence using a rodent model of depression. The results from these Specific Aims will enhance our understanding of the neuronal mechanisms underlying cocaine dependence and serve as a foundation for independence in the applicant'research career. PUBLIC HEALTH RELEVANCE: Findings in the proposed research will enhance our understanding of the neural mechanisms underlying cocaine dependence and may serve as a guidance in the efforts to develop better pharmacotherapeutics.